Intravenous Nitroglycerin In Patients Research Articles

Safety of prehospital intravenous bolus dose nitroglycerin in patients with acute pulmonary edema: A 4-year review.

Intravenous nitrates are a primary therapy for hypertensive congestive heart failure (CHF) with acute pulmonary edema (APE) in the hospital setting. Historically, sublingual nitrates are the mainstay of emergency medical services (EMS) pharmacologic therapy for these patients. We aimed to evaluate the safety of prehospital bolus dose intravenous nitroglycerin in patients with APE. This is a retrospective evaluation of EMS data between March 15, 2018, and March 15, 2022, where CHF with APE was suspected and bolus-dose intravenous nitroglycerin was administered. Protocol inclusion criteria were hypertension (systolic blood pressure [SBP]>160mmHg) and acute respiratory distress, with a presumption of decompensated CHF with APE. These patients received 1mg intravenous nitroglycerin, with the option to repeat once for ongoing distress if the SBP remained>160mmHg. The primary outcomes were adverse events, defined as hypotension (SBP<90mmHg), syncope, vomiting, or dysrhythmia. The final analysis included 235 patients. In patients receiving intravenous bolus nitroglycerin, the median (interquartile range [IQR]) initial and final EMS SBP values decreased from 198mmHg (180-218) to 168 (148-187), respectively. The median (IQR) pulse decreased from 108 (92-125) to 103 (86-119), and the median oxygen saturation increased from 89% (82-95) to 98% (96-99). Three episodes (1.3%) of asymptomatic hypotension occurred, and none required intervention. This study supports a favorable safety profile for prehospital bolus-dose intravenous nitroglycerin for decompensated CHF with APE. Blood pressure, heart rate, and oxygen saturation improvements are also demonstrated. Further, prospective studies are needed to confirm these findings.

Nitrate tolerance: a unifying hypothesis.

) production, endo-thelial dysfunction, and the neurohormonal activation that followlong-term administration of organic nitrates. In this issue ofCirculation, we will try to integrate these observations withother separate, and, to a certain extent, antagonistic hypothesesthat have been proposed for the development of nitrate toler-ance.

A randomized multicenter study comparing the efficacy and safety of intravenous milrinone and intravenous nitroglycerin in patients with advanced heart failure

A randomized, open-label, parallel-group design was used to determine the percentage of patients achieving improvements in predetermined baseline hemodynamic end points (>20% to 30% increase in cardiac index depending on baseline values and >25% decrease in pulmonary capillary wedge pressure), assessed at hour 0 (end of initial dose titration) and 1, 2, 4, 8, and 24 hours after the infusion of milrinone or nitroglycerin. In total, 125 patients (60 milrinone, 65 nitroglycerin) enrolled in this study, and 119 (58 milrinone, 61 nitroglycerin) were evaluable for the efficacy analysis. A significantly greater proportion of milrinone-treated patients reached (45% v 14%, P =.005) and maintained (24% v 6%, P =.026) hemodynamic goals than did nitroglycerin-treated patients; the time to achieve hemodynamic goals was significantly less in milrinone-treated patients (33 ± 2 v 54 ± 10 minutes, P <.001). Milrinone was also significantly more effective in decreasing systemic vascular resistance (P =.004), increasing stroke volume (P =.008), and improving global clinical status. Inodilator therapy with milrinone seems more efficacious in attaining sustained hemodynamic improvement than does pure intravenous vasodilator therapy with nitroglycerin in treating patients with decompensated heart failure.

Absence of vascular tolerance in conductance vessels after 48 hours of intravenous nitroglycerin in patients with coronary artery disease

We examined whether reflex neurohormonal constrictor forces attenuate the vasodilator action of nitroglycerin on large peripheral conductance vessels. Continuous nitroglycerin therapy is associated with the development of early tolerance with respect to its hemodynamic effects. It remains to be demonstrated whether vascular tolerance of large conductance vessels is an important contributory factor. Radial artery diameter and forearm blood flow velocity were measured before and 24 and 48 h after continuous intravenous nitroglycerin infusion (0.5 microgram/kg body weight per min) in 10 patients with coronary artery disease (mean age +/- SEM 59 +/- 4 years) by using a high resolution ultrasound device. Blood flow (ml/min) was calculated from mean blood flow velocity and cross-sectional area. Increasing concentrations of nitroglycerin led to a dose-dependent increase in radial artery diameter (maximal +24 +/- 2%) and heart rate. Forearm vascular resistance and forearm blood flow were unchanged. After 24 and 48 h of treatment, additional nitroglycerin did not further increase radial artery diameter, indicating that the nitroglycerin-induced dilation of the radial artery was maintained and was still maximal. In addition, radial artery diameter measured before and after 48 h of nitroglycerin infusion and after withdrawal of nitroglycerin in five additional patients showed that, after withdrawal, arterial diameter returned to baseline values within 35 min. Plasma renin activity and serum aldosterone and vasopressin levels increased significantly at 24 and 48 h, accompanied by a decrease in hematocrit. Continuous intravenous administration of nitroglycerin exerts a sustained vasodilator effect for 48 h in large conductance vessels. Neurohormonal activation and compensatory intravascular volume expansion do not attenuate the vasodilator effects of nitroglycerin on peripheral conductance vessels during the 1st 48 h of treatment.

Tolerance to intravenous nitroglycerin in patients with congestive heart failure: Role of increased intravascular volume, neurohumoral activation and lack of prevention with N-acetylcysteine

To better understand the mechanism of nitrate tolerance in patients with congestive heart failure, 13 patients received a 24 h infusion of nitroglycerin (1.5 micrograms/kg body weight per min) with or without N-acetylcysteine (225 mg/kg per 24 h). The infusions were separated by a 24 h nitrate-free interval. By the end of the nitroglycerin infusion, mean arterial pressure had returned to baseline values and there was a significant increase in ventricular filling pressures and systemic vascular resistance compared with values after 1 h of treatment. The simultaneous infusion of N-acetylcysteine had no effect on these changes. Although a strict fluid restriction of 1.5 liters/day was maintained for 1 week before and throughout the study, after 24 h of nitroglycerin infusion there was a significant and similar degree of hemodilution whether nitroglycerin was infused alone (9.1 +/- 4.3%) or with N-acetylcysteine (8.7 +/- 4.1%). This hemodilution corresponded to an increase in intravascular volume of 745 +/- 382 ml, most of which occurred during the 1st h. Plasma renin activity increased and plasma atrial natriuretic peptide decreased during the infusion. The results of this study suggest that nitrate tolerance is multifactorial. In addition to the previously described pharmacologic tolerance to the effect of nitroglycerin on vascular smooth muscle, a capillary fluid shift from the extravascular to intravascular space appears to be involved, especially during the 1st h of the infusion. A third mechanism, reflex neurohumoral activation, also seems to contribute to the genesis of nitroglycerin tolerance.

Role of Nitroglycerin in Acute Myocardial Infarction

Intravenous nitroglycerin lowers left ventricular filling pressure and systemic vascular resistance in patients with acute myocardial infarction. At lower infusion rates (less than 30 micrograms/min) nitroglycerin acts principally as a venodilator, while at higher infusion rates a balanced venous and arterial dilating effect is seen. Patients with left ventricular failure demonstrate increased or maintained stroke volumes, while patients without failure will show a decrease in stroke volume. All hemodynamic subgroups will show a reduction in left ventricular filling pressures and in electrocardiographic evidence of regional myocardial ischemia. Longer-term infusions (24-48 h) have been associated with a reduction in short-term mortality and evidence of myocardial preservation, as evidenced by improved left ventricular function or indices of infarct size. Studies comparing intravenous nitroglycerin and sodium nitroprusside have revealed increases in intercoronary collateral flow with nitroglycerin, in contrast to decreases with nitroprusside, suggesting a coronary steal with nitroprusside. Current clinical practice would recommend intravenous nitroglycerin as initial adjunctive therapy for patients receiving intravenous thrombolytic therapy and/or acute percutaneous transluminal angioplasty within 4-6 h of the onset of symptoms of acute myocardial infarction, with the goal of optimizing collateral flow until reperfusion can be accomplished. Patients treated later than 6 but less than 12-14 h after symptom onset should still receive intravenous nitroglycerin for 24-48 h with the hope of reducing infarct size. Likewise, congestive heart failure and arterial hypertension complicating acute infarctions as well as postinfarction unstable angina are additional current indications for the use of intravenous nitroglycerin in patients with acute myocardial infarction.

Prevention and Reversal of Nitrate Tolerance in Patients with Congestive Heart Failure

To evaluate possible mechanisms underlying the development of nitrate tolerance, we treated 35 patients who had severe chronic heart failure with a prolonged (48-hour) intravenous infusion of nitroglycerin (6.4 micrograms per kilogram of body weight per minute) given either continuously or intermittently (12-hour infusions separated by intervals of 12 hours). Intravenous nitroglycerin produced immediate hemodynamic benefits in all patients, but the magnitude of this improvement was greatly diminished after 48 hours of continuous therapy with the drug. This attenuation was accompanied by cross-tolerance to oral isosorbide dinitrate and by an increase in heart rate, plasma renin activity, and body weight. In contrast, intermittent therapy with intravenous nitroglycerin was not associated with a loss of hemodynamic efficacy or cross-tolerance to oral nitrates and was not accompanied by changes in neurohormonal activity or body weight. In eight patients in whom nitrate tolerance developed during continuous intravenous therapy, the administration of the sulfhydryl-containing compound N-acetylcysteine (200 mg per kilogram orally) restored the hemodynamic state toward that observed at the start of the infusion of nitroglycerin (partial reversal of tolerance). In contrast, N-acetylcysteine had little hemodynamic effect in patients who were not receiving nitroglycerin. These data support the hypothesis that neurohormonal activation and depletion of sulfhydryl groups may interact to cause the loss of hemodynamic efficacy that occurs during prolonged treatment with intravenous nitroglycerin in patients with heart failure. Evaluation of the suggested role of sulfhydryl depletion in the development of tolerance will, however, require direct studies of vascular tissue.

Effect of intravenous isosorbide dinitrate versus nitroglycerin on elevated pulmonary arterial wedge pressure during acute myocardial infarction

To compare the acute and sustained effect of intravenous isosorbide dinitrate to intravenous nitroglycerin in patients with acute myocardial infarction and elevated pulmonary artery wedge pressure, 111 patients were randomized and studied within 96 hours of admission to the coronary care unit. All patients had a pulmonary artery wedge pressure ≥18 mm Hg and received either isosorbide dinitrate (74 patients) or nitroglycerin (37 patients) for 24 to 48 hours. Blood pressure, heart rate, pulmonary artery wedge pressure, cardiac output, medication dose in micrograms per minute and retitration episodes were compared at baseline and at 6, 12, 18 and 24 hours. Both drugs significantly (p < 0.05) lowered pulmonary artery wedge pressure and blood pressure and increased cardiac output. Isosorbide dinitrate required fewer retitration episodes and less increases in dosage than nitroglycerin at 24 hours. In the patient with acute myocardial infarction complicated by high pulmonary artery wedge pressure who requires intravenous nitrates for 24 hours, isosorbide dinitrate may offer the benefit of a more stable hemodynamic effect.

Prevention and reversal of nitrate tolerance in patients with congestive heart failure.

To evaluate possible mechanisms underlying the development of nitrate tolerance, we treated 35 patients who had severe chronic heart failure with a prolonged (48-hour) intravenous infusion of nitroglycerin (6.4 micrograms per kilogram of body weight per minute) given either continuously or intermittently (12-hour infusions separated by intervals of 12 hours). Intravenous nitroglycerin produced immediate hemodynamic benefits in all patients, but the magnitude of this improvement was greatly diminished after 48 hours of continuous therapy with the drug. This attenuation was accompanied by cross-tolerance to oral isosorbide dinitrate and by an increase in heart rate, plasma renin activity, and body weight. In contrast, intermittent therapy with intravenous nitroglycerin was not associated with a loss of hemodynamic efficacy or cross-tolerance to oral nitrates and was not accompanied by changes in neurohormonal activity or body weight. In eight patients in whom nitrate tolerance developed during continuous intravenous therapy, the administration of the sulfhydryl-containing compound N-acetylcysteine (200 mg per kilogram orally) restored the hemodynamic state toward that observed at the start of the infusion of nitroglycerin (partial reversal of tolerance). In contrast, N-acetylcysteine had little hemodynamic effect in patients who were not receiving nitroglycerin. These data support the hypothesis that neurohormonal activation and depletion of sulfhydryl groups may interact to cause the loss of hemodynamic efficacy that occurs during prolonged treatment with intravenous nitroglycerin in patients with heart failure. Evaluation of the suggested role of sulfhydryl depletion in the development of tolerance will, however, require direct studies of vascular tissue.

The role of transdermal nitroglycerin in the treatment of coronary heart disease

Nitroglycerin has long been a mainstay of the treatment of ischemic cardiac pain. The introduction of transdermal formulations and in particular the development of controlled methods of delivery have been responsible for the renaissance of clinical interest in this simple and effective treatment. The pathophysiologic abnormality accompanying myocardial ischemia affords a natural theater for the exhibition of the therapeutic utility of these preparations and methods. The means whereby nitrates induce relaxation of vascular smooth muscle are not entirely clear, but their pharmacodynamic activities are perfectly plain. In the doses used in clinical practice, nitrates exert their predominant hemodynamic effects and therapeutic benefits through their peripheral vasodilator activities. This is particularly marked in veins, although in higher doses nitrates also dilate the larger systemic and coronary arteries. Criticisms of the efficacy of transdermal formulations of nitrates in the treatment of angina pectoris have arisen largely from uncritical acceptance of a small number of studies of questionable methodologic validity. Large-scale general practice studies have invariably found that transdermal nitrate delivery systems improve the quality of life in ambulant patients: anginal attacks are reduced with a minimum of side effects. The widespread acceptance of this novel form of drug delivery has stimulated its application in other therapeutic avenues. The efficacy of transdermal nitroglycerin in the suppression of silent ischemic attacks has been demonstrated. The maintenance of benefit initiated by intravenous nitroglycerin in patients with unstable angina also broadens the use of this method of nitrate delivery. In patients with acute myocardial infarction, whether complicated by left ventricular failure or not, the nitrates, and transdermal nitroglycerin in particular, appear to hold considerable promise. Improvement of hemodynamic abnormalities may cause reduction in infarct size and fewer life-threatening arrhythmias. Even survival may be extended. The utility of transdermal nitrates in the treatment of severe chronic heart failure is less certain. But the use of higher doses and an interval regimen of administration may hold promise for such patients. Naturally, more information is required before the overall therapeutic profile of this new method of controlled nitroglycerin delivery across the whole spectrum of coronary heart disease can be fully described. Fortunately, the high level of efficacy and safety of transdermal nitroglycerin demonstrated in the majority of reported studies encourages the pursuit of such an important therapeutic target.

Effects of dopamine with intravenous nitroglycerin in patients with severe left ventricular failure complicating myocardial infarction

Effects of dopamine with intravenous nitroglycerin in patients with severe left ventricular failure complicating myocardial infarction

Results of a randomized prospective trial of intraaortic balloon counterpulsation and intravenous nitroglycerin in patients with acute myocardial infarction

A randomized prospective clinical trial compared combined treatment with intraaortic balloon pumping and intravenous nitroglycerin for 4 to 5 days with routine clinical management in 20 patients with extensive myocardium at risk for infarction as evidenced by a thallium defect score of 7.0 units or greater. No significant differences in mortality or clinical outcome were observed between the 10 patients receiving the combined treatment and the 10 receiving routine management. In 14 patients two-dimensional echocardiograms obtained 6 to 24 hours after the onset of symptoms and at follow-up 6 to 16 days later (after completion of combined intraaortic balloon pumping plus nitroglycerin therapy) were analyzed to determine whether infarct segment or noninfarct segment lengths were affected by therapy. Among these 14 patients, 5 (3 receiving the combined therapy and 2 receiving routine management) demonstrated an increase in infarct segment length of greater than 1.0 cm. Mean infarct segment length increased 0.30 +/- 0.44 cm in patients receiving the combined therapy and 0.29 +/- 0.36 cm in patients on routine management (p = NS). In contrast, noninfarct segment length increased greater than 1.0 cm (mean increase 1.20 +/- 0.39) in five of seven patients on routine management but in none of 7 patients receiving intraaortic balloon pumping plus nitroglycerin therapy (mean decrease 0.22 +/- 0.20 cm) (p less than 0.05). No significant differences were noted in left ventricular ejection fraction, as measured by gated blood pool scintigraphy, or thallium perfusion defect score in a comparison of day 1 (pretreatment) with day 4 thallium or day 7 to 14 gated blood pool scintigrams. Thus, in patients with extensive myocardium at risk, it is unlikely that a reduction in mortality or a significant improvement in myocardial perfusion or ventricular function can be obtained by early intervention with intraaortic balloon pumping in combination with nitroglycerin. Although this combined therapy failed to prevent infarct segment lengthening (infarct expansion), the combined afterload-lowering effects of intraaortic balloon pumping and nitroglycerin did appear to prevent dilation or remodeling of noninfarcted segments during the first 2 weeks after acute myocardial infarction.

Nitroglycerin therapy in the management of pulmonary hypertensive disorders

Vasodilator therapy has not been effective in patients with pulmonary hypertension because most of the drugs that have been utilized in treating this disorder do not exert selective effects on the pulmonary circulation. Nonselective agents may cause predominant systemic vasodilation and lead to severe hypotension; they may elicit reflex activation of the sympathetic nervous system and further elevate pulmonary artery pressures; or they may exert depressant effects on right ventricular function and aggravate right-sided heart failure. Nitroglycerin has theoretic appeal as a vasodilator drug in patients with pulmonary hypertension because it exerts a direct effect on the pulmonary circulation in doses that do not affect systemic resistance vessels or the myocardium and do not activate neurohumoral reflexes. Furthermore, the drug uniquely reduces pulmonary artery pressures in addition to pulmonary vascular resistance due to its ability to dilate venous capacitance vessels. Preliminary studies with sublingual and intravenous nitroglycerin in patients with pulmonary hypertension have shown that the drug produces marked hemodynamic improvement and that clinical benefits follow long-term therapy with transcutaneous or oral nitrates. However, treatment may provoke hypotensive events in some patients and systemic hypoxemia in others; still others may fail to benefit because the pulmonary vasculature is unresponsive to any vasodilator stimulus. Further work is needed to define the benefits and risks of nitroglycerin therapy in patients with pulmonary hypertension.

A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction: Flaherty JT, Becker LC, Bulkley BH, et al. Circulation 1983; 68:576–588

A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction: Flaherty JT, Becker LC, Bulkley BH, et al. Circulation 1983; 68:576–588

Comparison of intravenous nitroglycerin and sodium nitroprusside in acute myocardial infarction

Initial studies from our institution demonstrated beneficial antiischemic effects of short-term infusion of intravenous nitroglycerin in patients with acute myocardial infarction. At lower doses, nitroglycerin was shown to be principally a venodilator; at higher doses, a mixed venous and arterial dilating effect was demonstrated. The acute hemodynamic effects of nitroglycerin varied in the presence or absence of left ventricular failure; patients with the most severe degree of left ventricular dysfunction had the most beneficial hemodynamic effect. Similar differential effects have been demonstrated for nitroprusside in other studies. A comparison of the arterial vasodilating potency of nitroglycerin and nitroprusside in patients in whom acute hypertension develops following coronary artery bypass surgery revealed that equal lowering of arterial pressure and systemic vascular resistance could be demonstrated in 85 percent of the patients with comparable infusion rates. Review of previous clinical and laboratory studies in animals, in which the effects of nitroglycerin and nitroprusside were compared, in most cases revealed opposite effects on intercoronary collateral flow and, thereby, opposite effects on the severity of regional ischemia. Our recently completed randomized placebo-controlled clinical trial employing a 48-hour infusion of nitroglycerin demonstrated a higher incidence of significant improvement in abnormalities noted on scintigraphy when nitroglycerin treatment was initiated within 10 hours of the onset of symptoms. Beneficial effects of early nitroglycerin treatment have also been demonstrated in previous clinical trials. In similar studies, which utilized nitroprusside infusions in patients with acute myocardial infarction, some investigators found an increase in short-term mortality with early nitroprusside treatment whereas others found benefit. The uniformly favorable results of the clinical trials that utilized intravenous nitroglycerin, although not necessarily supporting its routine use in all patients, would support a preference for nitroglycerin over nitroprusside for the treatment of congestive heart failure and/or acute hypertension complicating acute myocardial infarction.

Nitroglycerin Relaxes Large Airways

This study documents the effect of intravenous nitroglycerin (NTG) on tracheal smooth muscle in 12 patients undergoing coronary artery surgery. The pressure within a water-filled tracheal cuff was monitored continuously, as well as systemic and pulmonary arterial pressures. A significant decrease in cuff pressure after intravenous NTG (4.0 +/- 0.3 micrograms/kg) was detected before cardiopulmonary bypass (CPB). During CPB, with exclusion of the pulmonary arterial circulation, the tracheal cuff response to NTG administered into the oxygenator persisted and was not significantly different from that noted before CPB. Thus, the large airway (tracheal) response to NTG was independent of the pulmonary circulation and probably is mediated by the bronchial circulation. The response during CPB indicated that the tracheal smooth muscle retains tone and can respond to NTG even when the lungs are collapsed with no pulmonary arterial perfusion. These data were obtained from patients with no clinical evidence of reversible airway obstruction and indicate only that NTG relaxed human tracheal smooth muscle in vivo. These data do not demonstrate the efficacy of intravenous NTG in patients with asthma.

Effects of intravenous nitroglycerin on left ventricular function and ST segment changes in acute myocardial infarction.

It has been shown previously that 30-minute infusions of intravenous nitroglycerin in patients with acute myocardial infarction are able to lower left ventricular filling pressure and improve left ventricular function while lowering mean arterial pressure by only 7 mmHg (0.9 kPa). A decrease in sigmaST in praecordial ST segment mapping studies during nitroglycerin infusion in patients with anterior infarction suggested a decrease in the extent of myocardial ischaemia. In the present study, 30 patients with acute myocardial infarction received 1- to 3-hour infusions of intravenous nitroglycerin at infusion rates sufficient to lower mean arterial pressure by an average of 22 mmHg (2.9 kPa). An improvement in ventricular function was noted in that subgroup of patients with the msot severe left ventricular dysfunction. All patients with anterior myocardial infarction underwent serial ST segment mapping and, irrespective of the presence or absence of left ventricular failure, showed a decrease in sigmaST during nitroglycerin infusion (P less than 0.005). These findings suggest that infusion of nitroglycerin improves left ventricular function and/or alters left ventricular compliance in patients with left ventricular failure complicating myocardial infarction and furthermore decreases sigmaST in all patients, irrespective of the presence or absence of left ventricular failure, suggesting that the extent of myocardial ischaemia is decreased.